Several polypeptide growth factors have been identified with the ability to induce blood vessel development (angiogenesis), and the overall project goal is to utilize such growth factors to facilitate coronary collateral development in patients with ischemic heart disease. We have shown that basic fibroblast growth factor (bFGF), a pluripotent mitogen of mesodermally-derived cells, and vascular endothelial growth factor (VEGF), a specific endothelial cell mitogen, enhance coronary collateral development in dogs. VEGF is efficacious when administered repeatedly into the coronary circulation; bFGF is effective when administered repeatedly into the systemic arterial circulation or the coronary arteries. These routes of administration, although feasible in experimental animals, are not practical in human subjects. Most recently we have shown that two single doses of bFGF administered into the left main coronary artery enhance coronary collateral flow in dogs, a regimen that is feasible in human subjects. Dogs were subjected to gradual occlusion of the left circumflex coronary artery and randomized to receive bFGF 100 ug/kg or a vehicle control as an intracoronary bolus on one or two occasions (2 days between doses). Collateral perfusion was assessed during maximal coronary vasodilatation 17 days after treatment. Maximal collateral flow in dogs that received two doses of bFGF exceeded that of control dogs by 39% (P<0.0005). Based on these investigations, we began a Phase I clinical trial of bFGF in July, 1995, and that trial is ongoing. This is a randomized, double-blind study with dose escalation format to evaluate the safety and pharmacokinetics of intra-coronary bFGF in patients with coronary artery disease. Ongoing preclinical studies are designed to assess the potential of gene therapy for angiogenesis, alternate methods of bFGF administration, and the pharmacodynamics of bFGF.